This study evaluated the effect of Zoledronate (ZLN) on skeletal changes in ovariectomized (OVX) rhesus monkeys. Forty adult female rhesus monkeys (mean age 15.3 q 0.4) were randomly assigned to one control or four OVX groups. Three OVX groups received ZLN (0.5 ug/kg, 2.5 ug/kg, or 12.5 ug/kg) by a single weekly subcutaneous injection; the control and one OVX group received the saline vehicle (0). Dual-energy x-ray absorptiometry of the total body, lumbar spine, proximal femur, and mid and distal radius was done at 0, 13 and 26 weeks post-OVX. Serum and urine markers of skeletal turnover were measured at 0 and 13 weeks post-OVX. Data were analyzed byrepeated measures ANOVA. TBBMC Control OVX/0 OVX+0.5 OVX+2.5 OVX+12.5 0 wks 283 (10) 313 (18) 292 (15) 281 (13 288 (14) 13 wks 275 (10)* 293 (16) 276 (15) 275 (11) 290(14)a 26 wks 277 (11)a 286 (18) 272 (14) 277 (13)a 294(15)a LSBMD 0 wks .69 (.02) .74 (.03) .72 (.04) .68 (.03) .70(.03) 13 wks .70 (.02)* .69 (.02) .66 (.03) .66 (.03) .70(.03)* 26 wks .71 (.02) .70 (.02) .67 (.03) .70 (.03) .71(.04) TBBMC = total body bone mineral content (gramsqSEM)LSBMD = lumbar spine (L2-L4) bone mineral density g/cm2qSEM)Different from OVX/0 * = p < .05, = p < .005, a = p < .001. OVX-related loss was present (TBBMC and LSBMD) at 13 and 26 weeks. This loss was prevented by 12.5 and/or 2.5 ug/kg/wk ZLN but not 0.5 ug/kg/wk (Table). No OVX or ZLN treatment effect occurred at the femur or radius. At 13 weeks, serum skeletal alkaline phosphatase, osteocalcin, and urinary NTX were increased by OVX (p<.01). ZLN (2.5 and 12.5 ug/kg/wk) maintained these measures at or below control levels. In conclusion, OVX induces a 5-8% decline in TBBMC and LSBMD by 13 weeks in adult rhesus monkeys. ZLN prevents the OVX-induced bone turnover increase and bone loss. The adult rhesus monkey is a good model of estrogen-depletion bone loss. ZLN may prove to be effective in preventing postmenopausal bone loss.